Autoimmune disease occurs when a component of the immune system causes damage to the body (Harvey & Champe. Immunology. 2008. Williams & Wilkins, Philadelphia, Pa.). A number of autoimmune diseases exist which cause physical damage and greatly impact the quality of life of the sufferer. Several autoimmune diseases such as lupus may result in death if left unchecked. Current therapies for treatment of autoimmune disease have produced varying degrees of efficacy and in many cases unacceptable adverse event profiles. A clear unmet need exists for better treatments of autoimmune diseases.
Better therapeutics could result from treating the underlying pathologies of autoimmune diseases. The etiology of the various diseases is complex and differs from disease to disease. However, a number of autoimmune diseases can be partly attributed to the pathological actions of T-cells that either release substances which damage tissue or which activate other immune cells which cause damage. Psoriasis (Sabet et al. Experimental Dermatology. 2007. 16: 779-798), rheumatoid arthritis (Cope et al. Clin Exp Rheumatol. 2007. 25(5 Suppl 46):54-1), multiple sclerosis (MS) (Winquist et al. Biochemical Pharmacology. 2007. 74: 1321-1329) and type I diabetes (Mallone et al. Curr Diab Rep. 2008. 2:101-6) are examples of diseases in which T-cells are believed to play a contributory role to disease pathology. Several therapeutics including alefacept (Lev-Tov et al., Rev Recent Clin. Trials. 2006. 1:163-164), FK-506 and cyclosporine exert therapeutic actions by suppressing the activity of T-cells. The use of such T-cells suppressive drugs has been greatly limited to due to the global immunosuppressive nature of the agents. A need exists for a therapy which has the ability to suppress the pathological actions of T-cells without causing general immunosupression which leads to an increased risk of infection.
One potential strategy for selective T-cell suppression is to target activated effector memory T-cells while leaving central naïve T-cells untouched. One such strategy would be to target a component of T-cells which is upregulated in pathological effector memory cells and which is also critical for the activation of the T-cell. The potassium channel Kv1.3 has been hypothesized to be such a target (Chandy et al. TIPS. 2004. 25: 280-289). Kv1.3 is a critical component of the Calcium Release Activated Channel (CRAC) signaling pathway. In a simplified summary, upon activation of the CD3/T-cell receptor complex (e.g., by an antigen presenting cell), phospholipase C is activated which in turn causes release of calcium from the endoplasmic reticulum. The intracellular stores of calcium activate the CRAC channel which causes the influx of calcium and subsequent downstream signaling to the critical components of T-cell activation including calcineurin and nuclear factor of activated T-cells (NFAT).
In order for the continued influx of calcium through CRAC to continue, efflux of positively charged potassium is necessary to maintain the membrane potential. This potassium efflux can occur through either Kv1.3 or through the IKCa1 channel. The specific role of T-cells expressing high levels of Kv1.3 has been explored in several autoimmune diseases which are thought to be T-cell mediated. In MS patients, the number of Kv1.3 channels is upregulated in myelin-reactive T-cells and a specific Kv1.3 inhibitor decreased the activity of isolated pathogenic T-cells (Wulff et al. J. Clin. Invest. 2003. 111: 1703-1713). Furthermore, a Kv1.3 inhibitor was shown to be effective in prevention of death and in treatment of experimental autoimmune encephalitis (EAE) in rats, which is considered a standard animal model for MS (Beeton et al. Proc. Natl. Acad. Sci. USA. 2001. 98: 13942-13947). Likewise, Kv1.3 was shown to be upregulated in T-cells isolated from the synovial fluid of rheumatoid arthritis patients and a Kv1.3 inhibitor had the ability to decrease the activity of the isolated pathological cells (Beeton et al. Proc. Natl. Acad. Sci. USA. 2006. 98: 13942-13947). Beeton et al. further showed that a Kv1.3 inhibitor had the ability to decrease the amount of joint damage associated with pristane injection in a standard animal model of rheumatoid arthritis. Kv1.3 was also upregulated in islet reactive T-cells isolated from Type I Diabetes patients and Kv1.3 inhibitors decreased the activity of the pathogenic T-cells (Beeton et al. Proc. Nall. Acad. Sci. USA. 2006. 98: 13942-13947). Beeton et al. also showed that a Kv1.3 inhibitor could reduce the incidence of diabetes in a standard animal model. Azam et al. showed that Kv1.3 inhibitors have the ability to reduce ear swelling in rats following the animals' sensitization and subsequent exposure to oxazolone which is considered a model for both psoriasis and allergic contact dermatitis (Azam et al. J. Investigative Dermatology. 2007. 127: 1419-1429).
Kv1.3 has also been suggested as a target for type 2 diabeties, as Kv1.3 knockout mice had increased peripheral insulin sensivity and inhibition of Kv1.3 results in translocation of the glucose transporter GLUT4 to the plasma membrane (Xu et al. Proc. Natl. Acad. Sci. USA. 2004. 101: 3112-3117). The effects of Kv1.3 inhibition appeared to be additive to insulin in promoting GLUT4 transport (Li et al. Am J Physiol Cell Physiol. 2006. 290: C345-C351). A variant in the promoter of the Kv1.3 gene is also associated with impaired glucose tolerance and lower insulin sensitivity (Tschritter et al. The Journal of Clinical Endocrinology & Metabolism. 2006. 91: 654-658).
Accordingly, Kv1.3 is a promising target for several autoimmune diseases as well as type 2 diabetes and there exists a need for an inhibitor of Kv1.3 which has an adverse event and pharmacokinetic profile such that the inhibitor is therapeutically viable.